Project Summary/Abstract: Drug delivery represents a platform of tremendous potential in the field of nanomedicine. Delivery of therapeutic agents directly to target cells can drastically reduce the doses required for treatment and eliminate unwanted side effects and delivery to off-target tissues. To fully realize the potential of nanomedicince, safe, general, and efficient drug delivery nanoparticles must be developed which can be produced at relevant scales for study. Recently, the Johnson lab has developed a brush-arm star polymer (BASP) system that can successfully deliver a wide variety of different therapeutic agents in controllable ratios both in vivo and in vitro. Additionally, BASPs can be produced readily on kilogram scales, and are being currently evaluated in preclinical trials in mice. In this proposal, we aim to create a series of novel BASPs with controllable functionality to alter the pharmacokinetic properties for targeting new diseases and tissues for delivery. Using a new iterative peptide polymer (IPP) synthesis technique, we will be able to construct IPP appended BASPs that will allow for complete control over size, charge, chirality, and produce them at scales relevant for therapeutic applications. After synthesis of the BASPs we will extensively study their pharmacokinetic properties. By studying protein corona composition, uptake pathways, uptake kinetics, toxicity, immunogenicity, biodistribution and biological half-life we hope to derive structure-property relationships to develop BASPs that can target a variety of tissues via different mechanisms. There is a high demand to study drugless carriers to better understand their base properties before therapeutic use or use in disease models. Because the BASPs can be loaded with a variety of therapeutic agents (which do not alter its properties), we hope to ultimately develop a technology platform where different BASPs could be used to deliver any therapeutic agent to any tissue of interest in a controlled matter in response to this demand. Establishing the groundwork for these systems will hopefully create successful treatments for many diseases, and serve as a base for the development of even more advanced systems.